Published on Web 05/26/2004
Pd-Catalyzed Alkyl to Aryl Migration and Cyclization: An Efficient Synthesis of Fused Polycycles via Multiple C-H Activation Qinhua Huang, Alessia Fazio, Guangxiu Dai, Marino A. Campo, and Richard C. Larock* Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011 Received April 7, 2004; E-mail:
[email protected] Metal-catalyzed C-H bond activation is an area of considerable current interest.1 In particular, the ability of palladium to activate C-H bonds has been used extensively in organic synthesis.1b,2 Furthermore, the cyclopalladation of a pendant aromatic ring, a process that constitutes a good model for C-H activation, has led to many useful synthetic applications.3,4 For example, Lautens,5 Catellani,6 and Ca´mpora7 have previously reported interesting transformations that proceed through alkyl/aryl palladacycles. To date, only a couple of examples of complete alkyl to aryl palladium rearrangements via intramolecular C-H activation have been reported.4c,8 We have previously reported that intramolecular C-H activation in organopalladium intermediates derived from o-halobiaryls leads to a 1,4-palladium aryl to aryl migration and shown that such intermediates can be trapped by Heck reactions and intramolecular arylation.9 Herein, we wish to report 1,4-palladium alkyl to aryl migrations via through-space C-H activation, followed by intramolecular arylation or an intermolecular Heck reaction, which provide a very efficient way to synthesize fused ring systems. Our first attempts to effect 1,4-palladium alkyl to aryl migration employed compound 1. Under our usual palladium migration conditions reported earlier9 [0.25 mmol of aryl halide, 5 mol % Pd(OAc)2, 5 mol % bis(diphenylphosphino)methane (dppm), and 2 equiv of CsO2CCMe3 in DMF (4 mL)], aryl iodide 1 afforded an 88% yield of chromene 2 (entry 1, Table 1).10 This reaction appears to proceed as shown in Scheme 1 by a process that involves
Table 1. Synthesis of Fused Polycycles via 1,4-Palladium Alkyl to Aryl Migration, Followed by Intramolecular Arylationa
Scheme 1
a The reaction was carried out under our standard reaction conditions employing 0.25 mmol of aryl halide, 5 mol % Pd(OAc)2, 5 mol % dppm, and 2 equiv of CsO2CCMe3 in DMF (4 mL) at 100 °C unless otherwise noted. b Isolated yield. c The seven-membered Heck reaction product was obtained in a 5-10% yield. d The reaction was carried out at 90 °C.
palladium C-H activation with simultaneous 1,4-palladium alkyl to aryl migration via key arylpalladium intermediate A or B and subsequent intramolecular arylation by another Pd-catalyzed C-H activation. This through-space migration of a metal moiety between an alkyl and an aryl position amounts to an overall 1,4-palladium alkyl to aryl shift, which may involve an intermediate hydridopallada(IV)cycle4c,d generated by insertion of palladium into a neighboring C-H bond. Alternatively, Pd migration may proceed by generation of a pallada(II)cycle and subsequent protonation,7 although this seems unlikely in the present base and should proceed by cleavage of the arylpalladium bond. This process represents a very powerful new tool for the preparation of complex molecules, which may be difficult to prepare by any other present methodology. To test the effect of the linkage between the carbon-carbon double bond and the halide-substituted arene on this 1,4-palladium alkyl to aryl migration chemistry, aryl halides 3 and 5 were allowed 7460
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to react under our standard migration conditions. The results indicate that this migration/arylation process proceeds well with either an N or a C linkage (entries 2 and 3). We have also studied the regioselectivity of this migration by employing naphthalene derivatives 7, 9, and 11 (entries 4-6). The palladium migration/arylation occurs exclusively at the less sterically congested 3-position of these naphthalenes. The data in entries 4-6 indicate that the substituents on the aryl halide ring have a strong influence on the yield in this migration/arylation process. This migration process works best with electron-rich aromatics. Our finding that electron-rich arenes are superior to electron-deficient arenes in this alkyl to aryl migration via C-H activation is consistent with literature reports indicating that the ease of C-H activation by palladium parallels that of electrophilic aromatic substitution.11 It is important to note that this sequential migration/arylation reaction works well with more complex polycyclic aromatic compounds. For example, the reaction of compound 13 afforded pentacycle 14 in a 95% yield (entry 7), and tetrahydroquinoline 16 containing a 5,5-ring juncture has been successfully synthesized by this process in a 76% yield (entry 8). 10.1021/ja047980y CCC: $27.50 © 2004 American Chemical Society
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An interesting example of this migration involves the rearrangement of diaryl ether 17 to dibenzofuran 18 (entry 9). Mechanistically, the palladium must undergo a 1,4-palladium shift from an alkyl position to the 2-position of the diaryl ether, followed by arylation at the 2′-position of the diaryl ether (Scheme 2). This unique high yielding migration/arylation process provides a very powerful and efficient way to prepare complex fused benzofurans, carbazoles, and indenes. Scheme 2
We have also carried out the Pd-catalyzed double migration/ arylation of easily prepared aryl halide 19 and the complex fused dioxarubicenes 20 and 21 have been obtained in good yields (eq 1). This example further illustrates the efficiency of this migration/
arylation process for the construction of complex heterocycles and carbocycles using easily prepared starting materials. Another example of a reaction involving an alkyl to aryl palladium migration to generate a functionalized polycycle has been obtained from the reaction of 3-iodo-1-p-tosylindole (22) with norbornene under our standard Pd migration conditions (Scheme 3). The first step of this reaction involves the cis addition of an indol-3-ylpalladium iodide to norbornene,5-7 generating a stable alkylpalladium intermediate lacking cis β-hydrogens properly aligned for β-hydride elimination. This intermediate in turn undergoes a 1,4-palladium alkyl to aryl shift to the 2-position of the indole, followed by intramolecular cyclization onto the ptoluenesulfonyl moiety.12 This successful migration/arylation process indicates that the incorporated carbon-carbon double bonds can be introduced from external sources, which broadens the scope of this alkyl to aryl migration chemistry. Scheme 3
A mechanistically interesting question is whether the migrated arylpalladium(II) intermediate can be trapped by other traditional organopalladium chemistry and still affect synthetically useful chemistry. Thus, aryl halide 24 was allowed to react with ethyl acrylate and methyl vinyl ketone, and olefinated chromenes have been generated in good yields (eq 2). It appears that the intermolecular trapping of migrated arylpalladium intermediates by olefins
is much slower and less efficient than intramolecular arylation of the migrated arylpalladium intermediates. In conclusion, we have developed novel palladium alkyl to aryl migration methodology for the synthesis of complex fused polycycles, which employs sequential Pd-catalyzed C-H activation processes. The chemistry developed here works best with electronrich aromatics, which is in agreement with the idea that these palladium-catalyzed C-H activation reactions parallel electrophilic aromatic substitution. We are presently examining more closely the mechanism of this 1,4-palladium alkyl to aryl shift and further synthetic applications. Acknowledgment. We thank the donors of the Petroleum Research Fund, administered by the American Chemical Society, and the National Science Foundation, for partial support of this research. We are also grateful to Johnson Matthey, Inc. and Kawaken Fine Chemicals Co. for providing the palladium salts and Frontier Scientific Co. for donating the arylboronic acids used to prepare the starting materials. Supporting Information Available: General experimental procedures and spectroscopic characterization of all new products (PDF). This material is available free of charge via the Internet at http:// pubs.acs.org. References (1) (a) Crabtree, R. H. J. Chem. Soc., Dalton Trans. 2003, 21, 3985-3990. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 17311770. (c) Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997, 97, 28792932. (d) George, A. V. Trends Organomet. Chem. 1997, 2, 39-55. (2) (a) Li, C.-J. Acc. Chem. Res. 2002, 35, 533-538. (b) Fujiwara, Y. Handb. Organopalladium Chem. Org. Synth. 2002, 2, 2863-2871. (c) Negishi, E. Handb. Organopalladium Chem. Org. Synth. 2002, 2, 2905-2912. (d) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633-639. (3) For recent reviews, see: (a) Catellani, M. Synlett 2003, 298-313. (b) Dupont, J.; Pfeffer, M.; Spencer, J. Eur. J. Inorg. Chem. 2001, 19171927. (c) Dyker, G. Chem. Ber./Recl. 1997, 130, 1567-1578. (4) For palladium migration via palladacycles, see: (a) Karig, G.; Moon, M.T.; Thasana, N.; Gallagher, T. Org. Lett. 2002, 4, 3115-3118. (b) Tian, Q.; Larock, R. C. Org. Lett. 2000, 2, 3329-3332. (c) Ca´mpora, J.; Lo´pez, J. A.; Palma, P.; Valerga, P.; Spillner, E.; Carmona, E. Angew. Chem., Int. Ed. 1999, 38, 147-151. (d) Markies, B. A.; Wijkens, P.; Kooijman, H.; Spek, A. L.; Boersma, J.; van Koten, G. J. Chem. Soc., Chem. Commun. 1992, 1420-1423 (e) Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1985, 279, 225-232. (5) (a) Lautens M.; Pache, S. Org. Lett. 2003, 5, 4827-4830. (b) Lautens, M.; Paquin, J.-F.; Piguel, S.; Dahlmann, M. J. Org. Chem. 2001, 66, 8127-8134. (c) Lautens, M.; Piguel, S. Angew. Chem., Int. Ed. 2000, 39, 1045-1046. (6) (a) Faccini, F.; Motti, E.; Catellani, M. J. Am. Chem. Soc. 2004, 126, 78-79. (b) Catellani, M.; Mealli, C.; Motti, E.; Paoli, P.; Perez-Carren˜o, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336-4346 and references therein. (c) Catellani, M.; Motti, E.; Baratta, S. Org. Lett. 2001, 3, 3611-3614. (7) Ca´mpora, J.; Gutie´rrez-Puebla, E.; Lo´pez, J. A.; Monge, A.; Palma, P.; Del Rı´o, D.; Carmona, E. Angew. Chem., Int. Ed. 2001, 40, 3641-3644. (8) (a) Wang, L.; Pan, Y.; Jiang, X.; Hu, H. Tetrahedron Lett. 2000, 41, 725727. (b) Heck, R. F. J. Organomet. Chem. 1972, 37, 389-396. (9) (a) Campo, M. A.; Huang, Q.; Yao, T.; Tian, Q.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 11506-11507. (b) Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2002, 124, 14326-14327. (10) Attempts to cyclize o-iodoaryl allylic ethers to products having two fused five-membered rings have proven unsuccessful, presumably due to the greater distance the Pd must migrate in these systems as opposed to the six-membered ring intermediates and the strain present in the resulting products. (11) For mechanistic studies suggesting electrophilic species in intramolecular C-H activation by palladium, see: (a) Martin-Matute, B.; Mateo, C.; Cardenas, D. J.; Echavarren, A. M. Chem.sEur. J. 2001, 7, 2341-2348 and references therein. (b) Catellani, M.; Chiusoli, G. P. J. Organomet. Chem. 1992, 425, 151-154 and references therein. (12) For a similar Rh-catalyzed norbornyl to aryl migration using arylboronic acid precursors, see: Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. J. Am. Chem. Soc. 2000, 122, 10464-10465.
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